Aging and Immunity to Infections

描述（由申请人提供）：随着人类寿命的延长，越来越迫切需要了解衰老对感染免疫的影响，并制定预防或治疗策略来抵消与年龄相关的免疫衰退。持续病毒感染的免疫控制是一个与衰老相关的问题，正如有充分证据的例子所说明的那样，α -疱疹病毒，水痘-带状疱疹在老年人中重新激活，导致带状疱疹后神经痛（带状疱疹）。人类γ -疱疹病毒，爱泼斯坦-巴尔病毒和卡波西氏肉瘤相关疱疹病毒，是重要的人类病原体，与淋巴增生性疾病和各种恶性肿瘤有关，包括伯基特淋巴瘤、霍奇金病、鼻咽癌和卡波西氏肉瘤。因此，了解老年人控制这些感染的能力至关重要。在目前的提议中，我们将利用一个特征良好的小鼠模型HV68来研究衰老对这类重要的持久性病毒免疫控制的影响。越来越多的数据表明，CD4 T细胞、CDS T细胞和抗体都参与了幼鼠体内病毒潜伏期的免疫控制。我们的初步数据显示，病毒特异性抗体升在感染后可维持两年以上，但随着年龄的增长，中和活性逐渐下降。为了理解这一引人注目的新观察结果背后的功能含义和机制，在本补充应用中概述了三个具体目的。在目的1中，我们将确定下降的中和抗体对老年小鼠持续y疱疹病毒感染的免疫控制的功能影响。在Aim 2中，我们将确定抗体和病毒特异性B细胞和浆细胞的差异与老年小鼠中和活性下降有关。在目标3中，我们将确定中和抗体下降的机制。我们将确定年龄相关的CD4功能下降的影响，并确定下降的中和滴度是否是持久性病毒所独有的。这些研究不仅对老年人持续感染的免疫控制有意义，而且对理解体液免疫的长期维持机制也有一般意义。

DESCRIPTION (provided by applicant): With the increasing longevity of the human population, there is increased urgency to understand the consequences of aging on immunity to infections and to develop preventative or therapeutic strategies to counteract age-associated immune decline. Immune control of persistent viral infections is a problem associated with aging, as illustrated by the well-documented example of reactivation of the alpha-herpesvirus, varicella-zoster in the elderly, causing postherpetic neuralgia (Shingles). The human gamma-herpesviruses, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, are important human pathogens, associated with lymphoproliferative disorders and various maligancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and Kaposi's sarcoma. It is therefore critical that we understand the ability of aged individuals to control these infections. In the current proposal, we will exploit a well-characterized mouse model, HV68, to study the impact of aging on immune control of this important class of persistent viruses. Accumulating data suggest that CD4 T cells, CDS T cells and antibodies all contribute to immune control of viral latency in young mice. Our preliminary data show that virus-specific antibody liters are maintained for over two years after infection, but that there is a progressive decline in neutralizing activity with age. Proposed experiments to understand the functional implications and mechanisms underlying this striking and novel observation are outlined in three specific Aims in this supplemental application. In Aim 1, we will determine the functional impact of declining neutralizing antibodies for immune control of a persistent y-herpesvirus infection in aged mice. In Aim 2, we will identify differences in the antibody and virus-specific B cells and plasma cells associated with declining neutralizing activity in aged mice. In Aim 3, we will identify mechanisms underlying the decline in neutralizing antibodies. We will determine the impact of the age-associated decline in CD4 function and determine whether declining neutralizing titers are unique to persistent viruses. These studies have implications not only for immune control of persistent infections in aged individuals, but may also have general implications for understanding mechanisms for long-term maintenance of humoral immunity. As people age, their immune function declines. This is significant in terms of their ability to handle new infections and to be effectively vaccinated, but also for their ability to maintain immune control of persistent infections. The reactivation of the chicken pox virus in the elderly to cause Shingles is a classic example. In this project we will study the impact of age on immune control of another group of persistent viruses, the gamma-herpesviruses, which are associated with the development of several types of cancer. We will use a mouse model, in which we can carry out well-controlled studies not possible in humans.